Interplay of epithelial mechanics and neutrophil activation as a pathomechanism in refractory IBD and colorectal cancer patients

Descrizione del progetto

La dinamica epiteliale nelle malattie infiammatorie intestinali

Le malattie infiammatorie intestinali, tra cui la malattia di Crohn e la colite ulcerosa, sono caratterizzate da un’infiammazione a lungo termine del tratto gastrointestinale. Sebbene le terapie che neutralizzano la citochina pro-infiammatoria, fattore di necrosi tumorale, abbiano migliorato gli esiti clinici dei pazienti, molti individui non rispondono o sviluppano una resistenza nel corso del tempo. Sostenuto da programma di azioni Marie Skłodowska-Curie, il progetto INTERCONNECTIONS si concentra sui possibili cambiamenti meccanici subiti dalle cellule epiteliali intestinali che innescano l’infiammazione e la resistenza alla terapia, in base all’ipotesi secondo cui le dinamiche epiteliali influenzerebbero il modo in cui le cellule immunitarie, come i neutrofili, migrano attraverso i tessuti circostanti e li rimodellano. Scoprendo le modalità attraverso cui questi processi modellano la matrice extracellulare e il comportamento dei fibroblasti, il progetto mira a identificare nuovi bersagli molecolari per sviluppare trattamenti più efficaci delle malattie infiammatorie intestinali.

Obiettivo

Inflammatory bowel diseases (IBD) are a heterogeneous group of disorders characterized by gastrointestinal tract inflammation, being Crohn's Disease and Ulcerative Colitis, the most clinically abundant. IBD affects around 6.8 million people all over the world, being Europe the continent with the highest prevalence. Although anti-TNF-α monoclonal antibodies are a breakthrough therapy, almost 40% of IBD patients do not respond to therapy or acquire resistance. This leads to uncontrolled inflammation that, prolonged in time, constitutes a higher Colorectal Cancer risk. This justifies the current efforts to identify innovative therapy targets for IBD understanding of the molecular processes behind (personalized medicine). The fact that an increased intestinal permeability precedes the onset of inflammation possesses epithelial disruption as a potential etiological factor in IBD. Moreover, in recent years, several publications have highlighted that an impaired epithelial barrier is linked to resistance to therapy. Nevertheless, how altered epithelial mechanics can influence the structural properties of the extracellular matrix and immune cells migrating through it is not fully understood. On the other hand, the role of neutrophils as resistance-to-therapy players has emerged very recently. Then, we hypothesize that an alteration in epithelial cell mechanics constitutes a primary event that impacts the proliferation and behavior of the first immune cell responders: neutrophils. This would further contribute to ECM remodeling and fibroblasts polarization to IAFs (another mechanism implicated in therapy resistance). Then, INTERCONNECTIONS aims to elucidate how an altered epithelial dynamics constitutes a primary event that directly (through an altered transepithelial migration) or indirectly (affecting the mechanical framework) could promote the accumulation of activated neutrophils.